Substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines with adenosine receptor-binding activity and their use as cardiovascular preparations

ABSTRACT

This application relates to pyridine derivatives having the general structure 
     
       
         
         
             
             
         
       
     
     in which the several variables are as defined in the specification and claims, and to a process for preparing these compounds, a pharmacutical composition containing such compounds, and a method for using these materials for treatment of stable and unstable angina pectoris and atrial fibrillation.

This application is a 371 of PCT/EP02/02998 filed Mar. 19, 2002.

The present invention relates to novel2-thio-3,5-dicyano-4-aryl-6-aminopyridines, to a process for theirpreparation and to their use as medicaments.

Adenosine, a nucleoside consisting of adenine and D-ribose, is anendogenous factor having cell-protective activity, in particular undercell-damaging conditions with limited oxygen and substrate supply, suchas, for example, in the case of ischemia in various organs (for exampleheart and brain).

Adenosine is formed intracellularly as an intermediate during thedegradation of adenosine-5′-monophosphate (AMP) andS-adenosylhomocysteine, but it can be released from the cell, in whichcase it acts as a hormone-like substance or neurotransmitter by bindingto specific receptors.

Under normoxic conditions, the concentration of free adenosine in theextracellular space is very low. However, under ischemic or hypoxicconditions, the extracellular concentration of adenosine in the affectedorgans is increased dramatically. Thus, it is known, for example, thatadenosine inhibits platelet aggregation and increases the blood supplyto the coronary arteries. Furthermore, it acts on the heart rate, on therelease of neurotransmitters and on lymphocyte differentiation.

The aim of these actions of adenosine is to increase the oxygen supplyof the affected organs and/or to reduce the metabolism of these organsin order to adjust the metabolism of the organ to the blood supply ofthe organ under ischemic or hypoxic conditions.

The action of adenosine is mediated via specific receptors. To date,subtypes A1, A2a, A2b and A3 are known. The actions of these adenosinereceptors are mediated intracellularly by the messenger cAMP. In thecase of the binding of adenosine to the A2a or A2b receptors, theintracellular cAMP is increased via activation of the membrane-boundadenylate cyclase, whereas binding of adenosine to A1 or A3 receptorsresults in a decrease of the intracellular cAMP concentration viainhibition of adenylate cyclase.

According to the invention, “adenosine-receptor-selective ligands” aresubstances which bind selectively to one or more subtypes of theadenosine receptors, thus either mimicking the action of adenosine(adenosine agonists) or blocking its action (adenosine antagonists).

According to their receptor selectivity, adenosine-receptor-selectiveligands can be divided into different categories, for example ligandswhich bind selectively to the A1 or A2 receptors of adenosine and in thecase of the latter also, for example, those which bind selectively tothe A2a or the A2b receptors of adenosine. Also possible are adenosinereceptor ligands which bind selectively to a plurality of subtypes ofthe adenosine receptors, for example ligands which bind selectively tothe A1 and the A2, but not to the A3 receptors of adenosine.

The abovementioned receptor selectivity can be determined by the effectof the substances on cell lines which, after stable transfection withthe corresponding cDNA, express the receptor subtypes in question (seethe publication M. E. Olah, H. Ren, J. Ostrowski, K. A. Jacobson, G. L.Stiles, “Cloning, expression, and characterization of the unique bovineA1 adenosine receptor. Studies on the ligand binding site bysite-directed mutagenesis.” in J. Biol. Chem. 267 (1992) pages10764–10770, the disclosure of which is hereby fully incorporated by wayof reference).

The effect of the substances on such cell lines can be monitored bybiochemical measurement of the intracellular messenger cAMP (see thepublication K. N. Klotz, J. Hessling, J. Hegler, C. Owman, B. Kull, B.B. Fredholm, M. J. Lohse, “Comparative pharmacology of human adenosinereceptor subtypes—characterization of stably transfected receptors inCHO cells” in Naunyn Schmiedebergs Arch. Pharmacol. 357 (1998) pages1–9, the disclosure of which is hereby fully incorporated by way ofreference).

The “adenosine-receptor-specific” ligands known from the prior art aremainly derivatives based on natural adenosine (S.-A. Poulsen and R. J.Quinn, “Adenosine receptors: new opportunities for future drugs” inBioorganic and Medicinal Chemistry 6 (1998) pages 619–641; K. J.Broadley, “Drugs modulating adenosine receptors as potential therapeuticagents for cardiovascular diseases” in Exp. Opin. Ther. Patents 10(2000) pages 1669–1692). However, most of the adenosine ligands knownfrom the prior art have the disadvantage that their action is not reallyreceptor-specific, that their activity is less than that of naturaladenosine or that they have only very weak activity after oraladministration. Thus they are mainly used only for experimentalpurposes.

It is an object of the present invention to find or providepharmacologically active substances suitable for the prophylaxis and/ortreatment of various disorders, in particular disorders of thecardiovascular system (cardiovascular disorders), the substancespreferably acting as adenosine-receptor-selective ligands.

The present invention relates to compounds of the formula (I)

in which

-   R¹ and R² are attached to adjacent phenyl ring atoms and together    with the two ring carbon atoms form a 5- to 7-membered saturated or    partially unsaturated ring which may contain one or two heteroatoms    from the group consisting of N, O and/or S and which may be mono- or    disubstituted, independently of one another, by (C₁–C₄)-alkyl which    for its part may be substituted by hydroxyl, (C₁–C₄)-alkoxy or    phenyl, cyano, halogen or oxo,-   R³ represents (C₁–C₈)-alkyl which may be substituted up to three    times, independently of one another, by hydroxyl, (C₁–C₄)-alkoxy,    (C₃–C₇)-cycloalkyl, (C₂–C₄)-alkenyl, (C₂–C₄)-alkynyl, halogen or    (C₆–C₁₀)-aryloxy, (C₆–C₁₀)-aryl which may be substituted up to three    times, independently of one another, by halogen, nitro,    (C₁–C₄)-alkoxy, carboxyl, (C₁–C₄)-alkoxycarbonyl or mono- or    di-(C₁–C₄)-alkylamino, (C₁–C₈)-alkoxy which may be substituted by    hydroxyl, (C₁–C₄)-alkoxy, (C₃–C₆)-cycloalkyl, (C₂–C₄)-alkenyl,    (C₆–C₁₀)-aryl, 5- to 10-membered heteroaryl having up to three    heteroatoms from the group consisting of N, O and/or S,    (C₆–C₁₀)-aryloxy, halogen, cyano, (C₁–C₄)-alkoxycarbonyl, amino or    mono- or di-(C₁–C₄)-alkylamino, hydrogen, hydroxyl, halogen, nitro,    cyano or —NH—C(O)—R⁵,-    in which    -   R⁵ represents (C₁–C₈)-alkyl which may be substituted by hydroxyl        or (C₁–C₄)-alkoxy, (C₃–C₇)-cycloalkyl or (C₆–C₁₀)-aryl which may        be substituted up to three times, independently of one another,        by halogen, nitro, (C₁–C₄)-alkoxy, carboxyl,        (C₁–C₄)-alkoxycarbonyl or mono- or di-(C₁–C₄)-alkylamino,        and-   R⁴ represents (C₂–C₄)-alkenyl, (C₃–C₇)-cycloalkyl or (C₁–C₈)-alkyl,    where alkyl may be substituted up to three times, independently of    one another, by halogen, trifluoromethyl, trifluoromethylthio,    (C₃–C₇)-cycloalkyl hydroxyl, —CO—NH—R⁶, (C₁–C₄)-alkoxy,    (C₁–C₄)-alkoxycarbonyl, (C₂–C₄)-alkenyl, (C₆–C₁₀)-aryl or 5- to    10-membered heteroaryl having up to three heteroatoms and/or hetero    chain members from the group consisting of N, NO(N oxide), O and/or    S,-    where    -   aryl and heteroaryl for their part may be substituted up to        three times, independently of one another, by halogen,        trifluoromethyl, (C₁–C₄)-alkyl, which for its part may be        substituted by carboxyl or (C₁–C₄)-alkoxycarbonyl,        (C₁–C₄)-alkoxy, carboxyl, (C₁–C₄)-alkoxycarbonyl, amino, mono-        or di-(C₁–C₄)-alkylamino, nitro, cyano or hydroxyl,    -    and    -   R⁶ represents hydrogen, (C₁–C₈)-alkyl which may be substituted        by hydroxyl or (C₁–C₄)-alkoxy, (C₃–C₇)-cycloalkyl or        (C₆–C₁₀)-aryl which may be substituted up to three times,        independently of one another, by halogen, nitro, (C₁–C₄)-alkoxy,        carboxyl, (C₁–C₄)-alkoxycarbonyl or mono- or        di-(C₁–C₄)-alkylamino,        and their salts, hydrates, hydrates of the salt and solvates.

Depending on the substitution pattern, the compounds of the formula (I)can exist in stereoisomeric forms which are either like image and mirrorimage (enantiomers) or not like image and mirror image (diastereomers).The invention relates both to the enantiomers or diastereomers and totheir respective mixtures. The racemic forms, like the diastereomers,can be separated in a known manner into the stereoisomerically uniformcomponents. Likewise, the present invention also relates to the othertautomers of the compounds of the formula (I) and their salts.

Salts of the compounds of the formula (I) can be physiologicallyacceptable salts of the compounds according to the invention withmineral acids, carboxylic acids, or sulfonic acids. Particularpreference is given, for example, to salts with hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid,naphthalenedisulfonic acid, trifluoroacetic acid, acetic acid, propionicacid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acidor benzoic acid.

Salts which may be mentioned include salts with customary bases, suchas, for example, alkali metal salts (for example sodium salts orpotassium salts), alkaline earth metal salts (for example calcium saltsor magnesium salts) or ammonium salts, derived from ammonia or organicamines, such as, for example, diethylamine, triethylamine,ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine,dihydroabietylamine, 1-ephenamine or methylpiperidine.

According to the invention, hydrates or solvates are those forms of thecompounds of the formula (I) which, in solid or liquid state, form, byhydration with water or coordination with solvent molecules, a moleculecompound or a complex. Examples of hydrates are sesquihydrates,monohydrates, dihydrates or trihydrates. Likewise, the hydrates orsolvates of salts of the compounds according to the invention are alsosuitable.

Moreover, the invention also includes prodrugs of the compoundsaccording to the invention. According to the invention, prodrugs areforms of compounds of the formula (I) which for their part may bebiologically active or inactive, but which can be converted underphysiological conditions (for example metabolically or solvolytically)into the corresponding biologically active form.

In the context of the present invention, the substituents have, unlessdefined otherwise, the following meanings:

Halogen generally represents fluorine, chlorine, bromine or iodine.Preference is given to fluorine, chlorine or bromine. Very particularlypreferred are fluorine or chlorine.

(C₁–C₈)-Alkyl, (C₁–C₆)-alkyl and (C₁–C₄)-alkyl generally represent astraight-chain or branched alkyl radical having 1 to 8, 1 to 6 and 1 to4 carbon atoms, respectively. Preference is given to a straight-chain orbranched alkyl radical having 1 to 6 carbon atoms. Particular preferenceis given to a straight-chain or branched alkyl radical having 1 to 4carbon atoms. Examples which may be mentioned are: methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

(C₂–C₄-Alkenyl generally represents a straight-chain or branched alkylradical having 2 to 4 carbon atoms. Examples which may be mentioned are:vinyl, allyl, isopropenyl and n-but-2-en-1-yl.

(C₂–C₄)-Alkynyl generally represents a straight-chain or branchedalkynyl radical having 2 to 4 carbon atoms. Examples which may bementioned are: ethynyl, n-prop-2-yn-1-yl and n-but-2-yn-1-yl.

(C₁–C₈)-Alkoxy (C₁–C₆)-alkoxy and (C₁–C₄)-alkoxy generally represent astraight-chain or branched alkoxy radical having 1 to 8, 1 to 6 and 1 to4 carbon atoms, respectively. Preference is given to a straight-chain orbranched alkoxy radical having 1 to 6 carbon atoms. Particularpreference is given to a straight-chain or branched alkoxy radicalhaving 1 to 4 carbon atoms. Examples which may be mentioned are:methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,tert-butoxy.

(C₁–C₄)-Alkoxycarbonyl generally represents a straight-chain or branchedalkoxy radical having 1 to 4 carbon atoms which is attached via acarbonyl group. Examples which may be mentioned are: methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl andt-butoxycarbonyl.

In the context of the invention, mono- or di-(C₁–C₄)-alkylaminorepresents an amino group having one or two identical or differentstraight-chain or branched alkyl substituents each having 1 to 4 carbonatoms. Examples which may be mentioned are: methylamino, ethylamino,n-propylamino, isopropylamino, t-butylamino, N,N-dimethylamino,N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-n-propylamino and N-t-butyl-N-methylamino.

(C₃–C₇)-Cycloalkyl and (C₃–C₆)-cycloalkyl generally represent a cyclicalkyl radical having 3 to 7 and 3 to 6 carbon atoms, respectively.Preference is given to cyclic alkyl radicals having 3 to 6 carbon atoms.Examples which may be mentioned are: cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

(C₆–C₁₀)-Aryl generally represents an aromatic radical having 6 to 10carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

(C₆₋₁₀)-Aryloxy generally represents an aromatic radical as definedabove which is attached via an oxygen atom.

5- to 10-membered heteroaryl having up to 3 heteroatoms and/or heterochain members from the group consisting of N, NO(N oxide), O and/or Sgenerally represents a mono- or bicyclic, optionally benzo-fusedheteroaromatic which is attached via a ring carbon atom of theheteroaromatic, if appropriate also via a ring nitrogen atom of theheteroaromatic. Examples which may be mentioned are: pyridyl,pyridyl-N-oxide pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,oxdiazolyl, isoxazolyl, benzofuranyl, benzothienyl or benzimidazolyl.The corresponding heteroaromatics having fewer heteroatoms, such as, forexample, those having one or 2 heteroatoms from the group consisting ofN, O and/or S, or those having a smaller ring size, such as, forexample, 5- or 6-membered heteroaryl, are derived analogously from thisdefinition. In general, preference is given to 5- or 6-membered aromaticheterocycles having one or 2 heteroatoms from the group consisting of N,O and/or S. Examples which may be mentioned are: pyridyl, pyrimidyl,pyridazinyl, furyl, imidazolyl or thienyl.

5- to 7-membered heterocycle generally represents a saturated orpartially unsaturated, optionally benzo-fused heterocycle having up to 3heteroatoms from the group consisting of N, O and/or S. Examples whichmay be mentioned are: tetrahydrofuryl, pyrrolidinyl, pyrrolinyl,dihydropyridinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, hexahydropyranyl. The corresponding heterocycles havingfewer heteroatoms, such as, for example, one or 2 heteroatoms from thegroup consisting of N, O and/or S, or a smaller ring size, such as, forexample, 5- or 6-membered heterocyclyl, are derived analogously fromthis definition. Preference is given to saturated heterocycles having upto 2 heteroatoms from the group consisting of N, O and/or S, inparticular piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl.

Preference is given to compounds of the formula (I)

in which

-   R¹ and R² are attached to adjacent phenyl ring atoms and together    with the two ring carbon atoms form a 5- to 7-membered saturated    ring which may contain one or two heteroatoms from the group    consisting of N and/or O and which may be mono- or disubstituted,    independently of one another, by methyl which for its part may be    substituted by hydroxyl, (C₁–C₄)-alkoxy or phenyl, fluorine or    chlorine,-   R³ represents hydrogen or chlorine    and-   R⁴ represents (C₂–C₄)-alkenyl or (C₁–C₄)-alkyl, where alkyl may be    substituted up to two times, independently of one another, by    halogen, trifluoromethyl, trifluoromethylthio, (C₃–C₇)-cycloalkyl,    hydroxyl, —CO—NH—R⁶, (C₁–C₄)-alkoxy, (C₁–C₄)-alkoxycarbonyl,    (C₂–C₄)-alkenyl, (C₆–C₁₀)-aryl or 5- or 6-membered heteroaryl having    up to three heteroatoms from the group consisting of N, O and/or S,-    where    -   aryl and heteroaryl for their part may be substituted up to        three times, independently of one another, by halogen,        trifluoromethyl, (C₁–C₄)-alkyl which for its part may be        substituted by carboxyl or (C₁–C₄)-alkoxycarbonyl,        (C₁–C₄)-alkoxy, carboxyl, (C₁–C₄)-alkoxycarbonyl, nitro, cyano        or hydroxyl,    -    and    -   R⁶ represents hydrogen or (C₁–C₄)-alkyl,        and their salts, hydrates, hydrates of the salts and solvates.

Particular preference is given to compounds of the formula (I)

in which

-   R¹ and R² are attached to adjacent phenyl ring atoms and represent a    group

-   R³ represents hydrogen    and-   R⁴ represents propenyl, methyl, ethyl or n-propyl, where the alkyl    radicals for their part may be substituted up to two times,    independently of one another, by hydroxyl, methoxy, trifluoromethyl,    trifluoromethylthio, fluorine, imidazolyl, pyridyl, phenyl which for    its part may be substituted by fluorine, cyano, nitro, methoxy,    methoxycarbonyl (—C(O)—O—CH₃) or methoxycarbonylmethyl    (—CH₂—C(O)—CH₃), methoxycarbonyl (—C(O)—O—CH₃), amido (—C(O)—NH₂) or    N-methylamido (—C(O)—NH—CH₃),    and their salts, hydrates, hydrates of the salts and solvates.

Particular preference is also given to compounds of the formula (I) inwhich R¹ and R² are attached to adjacent phenyl ring atoms which arelocated in the para and meta positions to the point of attachment of thephenyl ring.

Particular preference is also given to compounds of the formula (I)

in which

-   R¹ and R² are attached to adjacent phenyl ring atoms and represent a    group

-   R³ represents hydrogen    and-   R⁴ represents propenyl, methyl, ethyl or n-propyl, where the alkyl    radicals for their part may be substituted up to two times,    independently of one another, by hydroxyl, methoxy, trifluoromethyl,    trifluoromethylthio, fluorine, imidazolyl, optionally    methyl-substituted thiazolyl, pyridyl, phenyl, which for its part    may be substituted by fluorine, cyano, nitro, methoxy,    methoxycarbonyl (—C(O)—O—CH₃) or methoxycarbonylmethyl    (—CH₂—C(O)—O—CH₃), methoxycarbonyl (—C(O)—O—CH₃), amido (—C(O)—NH₂)    or N-methylamido (—C(O)—NH—CH₃),    and their salts, hydrates, hydrates of the salts and solvates.

Particular preference is also given to compounds of the formula (I)

in which

-   R¹ and R² are attached to adjacent phenyl ring atoms and represent a    group

-   R³ represents hydrogen    and-   R⁴ represents methyl, ethyl or n-propyl, where the alkyl radicals    for their part may be substituted up to two times, independently of    one another, by hydroxyl, trifluoromethyl, trifluoromethylthio,    fluorine, imidazolyl, optionally methyl-substituted thiazolyl,    phenyl which for its part is substituted by cyano, nitro,    methoxycarbonyl (—C(O)—O—CH₃) or methoxycarbonylmethyl    (—CH₂—C(O)—O—CH₃), or amido (—C(O)—NH₂),    and their salts, hydrates, hydrates of the salts and solvates.

Particular preference is also given to the compounds of Examples 1, 3,5, 6, 7, 8, 9, 10, 11, 13, 14, 18, 19, 22, 24, 26, 28, 29, 30, 31, 33,34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54 and their salts, hydrates, hydrates of the salts and solvates.

The general or preferred radical definitions or illustrations givenabove can be combined with one another as desired, i.e. includingcombinations between the respective ranges and preferred ranges. Theyapply both to the end products and, correspondingly, to the precursorsand intermediates.

The present invention furthermore relates to a process for preparingcompounds of the formula (I), characterized in that

compounds of the formula (II)

in which

-   the radicals R¹, R² and R³ are as defined above,    are reacted in a solvent, if appropriate in the presence of a base,    with compounds of the formula (III)    R⁴—X  (III)    in which-   R⁴ is as defined above and-   X represents a leaving group, such as, for example, halogen, in    particular chlorine, bromine or iodine, or mesylate, tosylate,    triflate or 1-imidazolyl.

The process described above can be illustrated in an exemplary manner bythe formula scheme below:

Suitable solvents for the process according to the invention are allorganic solvents which are inert under the reaction conditions. Theseinclude alcohols such as methanol, ethanol and isopropanol, ketones,such as acetone and methyl ethyl ketone, acyclic and cyclic ethers, suchas diethyl ether and tetrahydofuran, esters, such as ethyl acetate orbutyl acetate, hydrocarbons, such as benzene, xylene, toluene, hexane orcyclohexane, dimethylformamide, acetonitrile, pyridine, dimethylsulfoxide (DMSO), chlorinated hydrocarbons, such as dichloromethane,chlorobenzene or dichloroethane. Another suitable solvent is water.Preference is given to dimethylformamide. It is also possible to usemixtures of the solvents mentioned above.

Suitable bases are the customary inorganic or organic bases. Thesepreferably include alkali metal hydroxides, such as, for example, sodiumhydroxide or potassium hydroxide, or alkali metal carbonates, such assodium carbonate or potassium carbonate or sodium bicarbonate, potassiumbicarbonate or sodium methoxide or potassium methoxide or sodiumethoxide or potassium ethoxide or potassium tert-butoxide or elseamides, such as sodium amide, lithium bis(trimethylsilyl)amide orlithium diisopropylamide, or organometallic compounds, such asbutyllithium or phenyllithium, or else amines, such as triethylamine andpyridine. Preference is given to alkali metal carbonates orbicarbonates, in particular to sodium carbonate or sodium bicarbonate.

Here, the base can be employed in an amount of from 1 to 10 mol,preferably from 1 to 5 mol, in particular from 1 to 4 mol, per mole ofthe compounds of the formula (II).

The reaction is generally carried out in a temperature range of from−78° C. to +120° C., preferably in the range from −78° C. to +40° C., inparticular at room temperature.

The reaction can be carried out at atmospheric, elevated or reducedpressure (for example in the range from 0.5 to 5 bar). In general, thereaction is carried out at atmospheric pressure.

Compounds of the formula (III) are commercially available, known to theperson skilled in the art or preparable by methods known from theliterature.

Compounds of the formula (II) are known to persons skilled in the art orpreparable by methods known from the literature. Reference may be made,in particular, to the following publications, the respective content ofwhich is expressly incorporated herein by way of reference:

-   -   Dyachenko et al., Russian Journal of Chemistry, Vol. 33, No. 7,        1997, pages 1014–1017 and Vol. 34, No. 4, 1998, pages 557–563;    -   Dyachenko et al., Chemistry of Heterocyclic Compounds, Vol. 34,        No. 2, 1998, pages 188–194;    -   Qintela et al., European Journal of Medicinal Chemistry, Vol.        33, 1998, pages 887–897;    -   Kandeel et al., Zeitschrift für Naturforschung 42b, 107–111        (1987).

Additionally, compounds of the formula (II) may also be prepared, forexample, from compounds of the formula (IV) by reaction with an alkalimetal sulfide.

This preparation method may be illustrated in an exemplary manner by theformula scheme below:

The alkali metal sulfide used is preferably sodium sulfide in an amountof from 1 to 10 mol, preferably from 1 to 5 mol, in particular from 1 to4 mol, per mole of the compounds of the formula (IV).

Suitable solvents are all organic solvents which are inert under thereaction conditions. These include N,N-dimethylformamide,N-methylpyrrolidinone, pyridine and acetonitrile. Preference is given toN,N-dimethylformamide. It is also possible to use mixtures of thesolvents mentioned above.

The reaction is generally carried out in a temperature range of from+20° C. to +150° C., preferably in the range of from +20° C. to +120°C., in particular at from +60° C. to +100° C.

The reaction can be carried out at atmospheric, elevated or reducedpressure (for example in the range from 0.5 to 5 bar). In general, thereaction is carried out at atmospheric pressure.

Compounds of the formula (IV) are known to the person skilled in the artor preparable by customary methods known from the literature. Referencemay be made, in particular, to the publication Kambe et al., Synthesis,531 (1981), the content of which is expressly incorporated here by wayof reference.

Surprisingly, the compounds of the formula (I) have an unforeseeableuseful pharmacological activity spectrum and are therefore suitable inparticular for the prophylaxis and/or treatment of disorders.

The compounds of the formula (I) are suitable for the prophylaxis and/ortreatment of a number of disorders, such as, for example, in particulardisorders of the cardiovascular system (cardiovascular disorders).

In the context of the present invention, cardiovascular disorders are tobe understood as meaning, in particular, for example the followingdisorders: coronary heart disease, hypertension (high blood pressure),restenosis after balloon dilation of peripheral blood vessels,arteriosclerosis, tachycardia, arrhythmias, peripheral vasculardisorders and cardiovascular disorders, stable and unstable anginapectoris and atrial fibrillation.

The compounds of the formula (I) are furthermore also particularlysuitable, for example, for reducing the size of the myocardial areaaffected by an infarct.

The compounds of the formula (I) are furthermore particularly suitable,for example, for the prophylaxis and/or treatment of thromboembolicdisorders and ischemias, such as myocardial infarction, stroke andtransitory ischemic attacks.

Further areas of indication for which the compounds of the formula (I)are suitable are, for example, in particular the prophylaxis and/ortreatment of disorders of the urogenital system, such as, for example,an irritable bladder, erectile dysfunction and female sexualdysfunction, but additionally also the prophylaxis and/or treatment ofinflammatory disorders, such as, for example, asthma and inflammatorydermatoses, of neuroinflammatory disorders of the central nervoussystem, such as, for example, disorders after stroke, Alzheimer'sdisease, and furthermore also neurodegenerative disorders, such asParkinson's disease, and also pain and cancer.

A further area of indications is, for example, in particular theprophylaxis and/or treatment of disorders of the respiratory tract, suchas, for example, asthma, chronic bronchitis, pulmonary emphysema,bronchiectases, cystic fibrosis (mucoviscidosis) and pulmonaryhypertension.

The compounds of the formula (I) are furthermore also suitable, forexample, in particular for the prophylaxis and/or treatment of liverfibrosis and liver cirrhosis.

Finally, the compounds of the formula (I) are in particular alsosuitable, for example, for the prophylaxis and/or treatment of diabetes,in particular diabetes mellitus.

The present invention also relates to the use of the compounds of theformula (I) for preparing medicaments and pharmaceutical compositionsfor the prophylaxis and/or treatment of the clinical pictures mentionedabove.

The present invention furthermore relates to a method for theprophylaxis and/or treatment of the clinical pictures mentioned aboveusing the compounds of the formula (I).

The pharmaceutical activity of the compounds of the formula (I)mentioned above can be explained by their activity as selective ligandson individual subtypes or a plurality of subtypes of the adenosinereceptors, in particular as selective ligands on adenosine A1, adenosineA2a and/or adenosine A2b receptors, preferably as selective ligands onadenosine A1 and/or adenosine A2b receptors.

In the context of the present invention, adenosine receptor ligands arereferred to as being “selective” if, firstly, they are clearly active onone or more adenosine receptor subtypes and, secondly, the activity thatcan be observed on one or more other adenosine receptor subtypes isconsiderably weaker, if present at all, where, with respect to the testmethods for selectivity of action, reference is made to the test methodsdescribed in Section A. II.

One advantage of the compounds of the formula (I) according to theinvention is that they are more selective than adenosine receptorligands of the prior art.

In particular, compounds of the formula (I) in which R¹ and R² representa group —O—CH₂—O—, —O—CH₂—CH₂—O— or —O—CH(CH₂OH)—CH₂—O— generally act asagonists on adenosine A1 receptors.

In particular, compounds of the formula (I) in which R¹ and R² representa group —O—CF₂—O— generally act as antagonists on adenosine A1receptors.

The receptor selectivity can be determined by biochemical measurement ofthe intracellular messenger cAMP in the transfected cells whichspecifically only express one subtype of the adenosine receptors. Here,what is observed is, in the case of A2a and A2b agonists (couplingpreferably via Gs proteins) and in the case of A2a and A2b antagonistsis an increase of the intracellular cAMP concentration and a decrease ofthe intracellular cAMP concentration, respectively, followingprestimulation with adenosine or adenosine-like substances (see thepublications B. Kull, G. Arslan, C. Nilsson, C. Owman, A. Lorenzen, U.Schwabe, B. B. Fredholm, “Differences in the order of potency foragonists but not antagonists at human and rat adenosine A2A receptors”,Biochem. Pharmacol., 57 (1999) pages 65–75; and S. P. Alexander, J.Cooper, J. Shine, S. J. Hill, “Characterization of the human brainputative A2B adenosine receptor expressed in Chinese hamster ovary(CHO.A2B4) cells”, Br. J. Pharmacol., 119 (1996) pages 1286–90, therespective content of which is expressly incorporated herein by way ofreference). Correspondingly, A1 agonists (coupling preferably via Giproteins) and A1 antagonists result in a decrease and increase,respectively, of the cAMP concentration.

Thus, compounds of the formula (I) which bind selectively to adenosineA1 receptors are preferably suitable for myocard protection and for theprophylaxis and/or treatment of tachycardia, atrial arrhythmias, cardiacinsufficiency, myocardial infarction, acute kidney failure, diabetes,and pain.

Compounds of the formula (I) which bind selectively to adenosine A2areceptors are preferably suitable for the prophylaxis and/or treatmentof thromboembolic disorders, of neurodegenerative disorders such asParkinson's disease and for wound healing.

Compounds of the formula (I) which bind selectively to adenosine A2breceptors are preferably suitable for the prophylaxis and/or therapy ofliver fibrosis, of myocardial infarction, of neuroinflammatorydisorders, of Alzheimer's disease, of urogenital incontinence and ofdisorders of the respiractory tract, such as, for example, asthma andchronic bronchitis.

The present invention also provides medicaments and pharmaceuticalpreparations comprising at least one compound of the formula (I),preferably together with one or more pharmaceutically acceptableauxiliavies or carriers, and their use for the above mentioned purposes.

Suitable for administering the compounds of the formula (I) are allcustomary administration forms, i.e. oral, parenteral, inhalative,nasal, sublingual, rectal, local, such as, for example, in the case ofimplants or stents, or external, such as, for example, transdermal. Inthe case of parenteral administration, particular mention may be made ofintravenous, intramuscular and subcutaneous administration, for exampleas a subcutaneous depot. Particular preference is given to oraladministration.

Here, the active compounds can be administered on their own or in theform of preparations. Suitable preparations for oral administration areinter alia tablets, capsules, pellets, sugar-coated tablets, pills,granules, solid and liquid aerosols, syrups, emulsions, suspensions andsolutions. Here, the active compound has to be present in such aquantity that a therapeutic effect is obtained. In general, the activecompound can be present in a concentration of from 0.1 to 100% byweight, in particular from 0.5 to 90% by weight, preferably from 5 to80% by weight, i.e. the active compound should be present in quantitiessufficient to achieve the dosage range mentioned.

To this end, the active compounds can be converted in a manner known perse to the customary preparations. This is achieved using inert nontoxicpharmaceutically suitable carriers, auxiliaries, solvents, vehicles,emulsifiers and/or dispersants.

Auxiliaries which may be mentioned are, for example: water, nontoxicorganic solvents, such as, for example, paraffins, vegetable oils (forexample sesame oil), alcohols (for example ethanol, glycerol), glycols(for example polyethylene glycol), solid carriers, such as natural orsynthetic ground minerals (for example talc or silicates), sugars (forexample lactose), emulsifiers, dispersants (for examplepolyvinylpyrrolidone) and glidants (for example magnesium sulfate).

In the case of oral administration, tablets may, of course, also containadditives such as sodium citrate, together with adjuvants such asstarch, gelatin and the like. Aqueous preparations for oraladministration may furthermore be admixed with flavor enhancers orcolorants.

In general, it has been found to be advantageous to administer, in thecase of parenteral administration, quantities of from about 0.1 to about10 000 μg/kg, preferably from about 1 to about 1000 μg/kg, in particularfrom about 1 μg/kg to about 100 μg/kg, of body weight, to obtaineffective results. In the case of oral administration, the quantity isfrom about 0.1 to about 10 mg/kg, preferably from about 0.5 to about 5mg/kg, in particular from about 1 to about 4 mg/kg, of body weight.

In spite of this, it may still be required, depending on body weight,administration route, individual response to the active compound, thetype of preparation and the time or interval at which administrationtakes place, to deviate from the quantities mentioned.

The present invention is illustrated by the following examples, which donot restrict the invention in any way.

A. Assessing Physiological Activity

I. Detectiny the Cardiovascular Effect

Langendorff Heart of the Rat:

After the thorax has been opened, the heart is rapidly removed fromanesthetized rats and introduced into a conventional Langendorffapparatus. The coronary arteries are perfused at constant volume (10ml/min), and the resulting perfusion pressure is recorded by way of anappropriate pressure sensor. In this set-up, a decrease in the perfusionpressure corresponds to a relaxation of the coronary arteries. At thesame time, the pressure which the heart develops during each contractionis measured by way of a balloon, which has been introduced into the leftventricle, and a second pressure sensor. The frequency of the heart,which is beating in isolation, is calculated from the number ofcontractions per time unit.

II. Assessing the Receptor Selectivity

a) Adenosine A1, A2a, A2b and A3 Receptor Selectivity

Cells of the CHO (Chinese Hamster Ovary) permanent cell line aretransfected stably with the cDNA for the adenosine receptor subtypes A1,A2a, A2b and A3. The binding of the substances to the A2a or A2breceptor subtypes is determined by measuring the intracellular cAMPcontent in these cells using a conventional radioimmunological assay(cAMP RIA).

When the substances act as agonists, the binding of the substances isexpressed as an increase in the intracellular content of cAMP. Theadenosine-analogous compound NECA (5-N-ethylcarboxamido-adenosine),which binds all adenosine receptor subtypes with high affinity but notselectively and possesses an agonistic effect, is used as the referencecompound in these experiments (Klotz, K. N., Hessling, J., Hegler, J.,Owman, C., Kull, B., Fredholm, B. B., Lohse, M. J., Comparativepharmacology of human adenosine receptor subtypes—characterization ofstably transfected receptors in CHO cells, Naunyn Schmiedebergs ArchPharmacol, 357 (1998), 1–9).

The adenosine receptors A1 and A3 are coupled to a G_(i) protein, i.e.stimulation of these receptors leads to inhibition of the adenylatecyclase and consequently to a lowering of the intracellular cAMP level.In order to identify A1/A3 receptor agonists, the adenylate cyclase isstimulated with forskolin. However, an additional stimulation of theA1/A3 receptors inhibits the adenylate cyclase, which means that A1/A3receptor agonists can be detected by a comparatively low content of cAMPin the cell.

In order to detect an antagonistic effect on adenosine receptors, therecombinant cells which are transfected with the corresponding receptorare prestimulated with NECA and the effect of the substances on reducingthe intracellular content of cAMP occasioned by this prestimulation isinvestigated. XAC (xanthine amine congener), which binds to alladenosine receptor subtypes with high affinity and possesses anantagonistic effect, is used as the reference compound in theseexperiments (Müller, C. E., Stein, B., Adenosine receptor antagonists:structures and potential therapeutic applications, CurrentPharmaceutical Design, 2 (1996) 501–530).

b) Adenosine A1, A2a, A2b Receptor Selectivity

Cells of the CHO (Chinese Hamster Ovary) permanent cell line aretransfected stably with the cDNA for the adenosine receptor subtypes A1,A2a and A2b. The adenosine A1 receptors are coupled to the adenylatecyclase by way of G_(i) proteins, while the adenosine A2a and A2breceptors are coupled by way of Gs proteins. In correspondence withthis, the formation of cAMP in the cell is inhibited or stimulated,respectively. After that, expression of the luciferase is modulated byway of a cAMP-dependent promoter. The luciferase test is optimized, withthe aim of high sensitivity and reproducibility, low variance and goodsuitability for implementation on a robot system, by varying severaltest parameters, such as cell density, duration of the growth phase andthe test incubation, forskolin concentration and medium composition. Thefollowing test protocol is used for pharmacologically characterizingcells and for the robot-assisted substance test screening:

The stock cultures are grown, at 37° C. and under 5% CO₂, in DMEM/F12medium containing 10% FCS (fetal calf serum) and in each case split 1:10after 2–3 days. The test cultures are seeded in 384-well plates at therate of from 1 000 to 3 000 cells per well and grown at 37° C. forapprox. 48 hours. The medium is then replaced with a physiologicalsodium chloride solution (130 mM NaCl, 5 mM KCL, 2 mM CaCl₂, 20 mMHEPES, 1 mM MgCl₂.6H₂O, 5 mM NaHCO₃, pH 7.4). The substances, which aredissolved in DMSO, are diluted 1:10 three times with this physiologicalsodium chloride solution and pipetted into the test cultures (maximumfinal concentration of DMSO in the test mixture: 0.5%). In this way,final substance concentrations of, for example, from 5 μM to 5 nM areobtained. 10 minutes later, forskolin is added to the A1 cells and allthe cultures are subsequently incubated at 37° C. for 4 hours. Afterthat, 35 μl of a solution which is composed of 50% lysis reagent (30 mMdisodium hydrogenphosphate, 10% glycerol, 3% TritonX100, 25 mM Tris HCl,2 mM dithiothreitol (DTT), pH 7.8) and 50% luciferase substrate solution(2.5 mM ATP, 0.5 mM luciferin, 0.1 mM coenzyme A, 10 mM tricine, 1.35 mMMgSO₄, 15 mM DTT, pH 7.8) are added to the test cultures, the plates areshaken for approx. 1 minute and the luciferase activity is measuredusing a camera system.

B. Working Examples

Abbreviations Used:

-   DMSO dimethyl sulfoxide-   HPLC high pressure, high performance liquid chromatography-   NMR nuclear magnetic resonance spectroscopy-   DMF dimethylformamide

EXAMPLE 12-Amino-4-(1,3-benzodioxol-5-yl)-6-(2-hydroxyethyl)sulfanyl-3,5-pyridinedicarbonitrile

75 mg (0.19 mmol) of2-amino-4-(1,3-benzodioxol-5-yl)-6-sulfanyl-3,5-pyridinedicarbonitrile[prepared analogously to Dyachenko et al., Russian Journal of Chemistry33 (7), 1014–1017 (1997); 34 (4), 557–563 (1998)] and 47 mg (0.38 mmol)of 2-bromoethanol and 63 mg (0.75 mmol) of sodium bicarbonate arestirred in 1 ml of DMF at room temperature overnight. Water is thenadded, and the precipitated product is filtered off with suction anddried under reduced pressure.

Yield: 55 mg (85.8% of theory)

Mass spectrum: molar mass required 340, found [M+H]⁺=341

¹H-NMR spectrum [DMSO-d₆]: δ=3.4 [2H] tr; 3.65 [2H] q; 5.0 [1H] tr; 6.15[2H] s; 7.0–7.2 [3H] m; 7.8–8.2 [2H] s broad

EXAMPLE 22-Amino-4-(1,3-benzodioxol-5-yl)-6-(benzylsulfanyl)-3,5-pyridinedicarbonitrile

The reaction was carried out analogously to Example 1.

Yield: 74 mg (100% of theory)

Mass spectrum: molecular mass required 386, found [M+H]⁺=387

¹H-NMR spectrum [DMSO-d₆]: δ=4.5 [2H] s; 6.15 [2H] s; 7.0–7.2 [3H] m;7.3–7.6 [5H] m; 7.8–8.2 [2H] s broad.

EXAMPLE 32-Amino-4-(2,2-difluoro-1,3-benzodioxol-5-yl)-6-[(2-pyridinylmethyl)sulfanyl]-3,5-pyridinedicarbonitrile

The reaction was carried out analogously to Example 1.

Yield: 50 mg (79% of theory)

Mass spectrum: molar mass required 423, found [M+H]⁺=424

¹H-NMR spectrum [DMSO-d₆]: δ=4.6 [2H] s; 6.8 [1H] m; 6.95 [1H] dd;7.6–7.8 [4H] m; 7.9–8.4 [2H] s broad; 8.55 [1H] d.

EXAMPLE 42-Amino-6-(benzylsulfanyl)-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3,5-pyridinedicarbonitrile

100 mg (0.32 mol) of2-amino-6-sulfanyl-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3,5-pyridinedicarbonitrile[prepared analogously to Dyachenko et al., Russian Journal of Chemistry33 (7), 1014–1017 (1997); 34 (4), 557–563 (1998)], 110 mg (0.64 mmol) ofbenzyl bromide and 108 mg (1.29 mmol) of sodium bicarbonate are stirredin 2 ml of DMF at room temperature for 5.5 h. Water is then added andthe mixture is extracted three times with ethyl acetate. The combinedorganic phases are dried with magnesium sulfate and concentrated underreduced pressure. The residue is taken up in diethyl ether, giving,after reconcentration, a crystalline product.

Yield: 106 mg (82% of theory)

Mass spectrum: molar mass required 400, found [M+H]⁺=401

¹H-NMR spectrum [DMSO-d₆]: δ=4.3 [4H] m; 4.5 [2H] s; 6.9–7.1 [3H] m;7.2–7.4 [3H] m; 7.5 [2H] m; 7.8–8.2 [2H] s broad.

EXAMPLE 52-Amino-6-((2-hydroxyethyl)sulfanyl)-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3,5-pyridinedicarbonitrile

The reaction was carried out analogously to Example 1.

Yield: 15 mg (13% of theory)

Mass spectrum: molar mass required 354, found [M+H]⁺=355

¹H-NMR spectrum [DMSO-d₆]: δ=3.4 [2H] tr; 3.65 [2H] q; 4.3 [4G] s; 5.0[1H] tr; 7.0–7.1 [3H] m; 7.8–8.1 [2H] s broad.

EXAMPLE 62-Amino-6-[(2-hydroxyethyl)sulfanyl]-4-[2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-3,5-pyridinedicarbonitrile

30 mg (0.09 mmol) of2-amino-6-sulfanyl-4-[2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-3,5-pyridinedicarbonitrile[prepared analogously to Dyachenko et al., Russian Journal of Chemistry33 (7), 1014–1017 (1997); 34 (4), 557–563 (1998)], 22 mg (0.18 mmol) of2-hydroxyethyl bromide and 29 mg (0.35 mmol) of sodium bicarbonate arestirred in 1.5 ml of DMF at room temperature overnight. The reactionsolution is purified directly by preparative HPLC on reversed-phasesilica gel.

Yield: 2.1 mg (6% of theory)

Mass spectrum: molar mass required 384, found [M+H]⁺=385

¹H-NMR spectrum [DMSO-d₆]: δ=3.3 [2H] tr; 3.65 [4H] m; 4.05 [1H] dd; 4.3[1H] m; 4.4 [1H] dd; 5.0 [1H] tr; 5.15 [1H] trm; 7.0–7.1 (3H] m; 7.8–8.1[2H] s broad.

EXAMPLE 72-Amino-6-[benzylsulfanyl]-4-[2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-3,5-pyridinedicarbonitrile

The reaction was carried out analogously to Example 6.

Yield: 4.6 mg (12% of theory)

Mass spectrum: molar mass required 430, found [M+H]⁺=431

¹H-NMR spectrum [DMSO-d₆]: δ=3.7 [2H] m; 4.05 [1H] dd; 4.3 [1H] m; 4.4[1H] dd; 4.5 [2H] s; 5.1 [1H] tr; 7.0–7.1 [3H] m; 7.2–7.6 [5H] m;7.8–8.1 [2H] s broad.

The compounds listed in the table below (Examples 8 to 54) are preparedanalogously. The identity of the compounds is detected by LC-MS.

Example Molar mass [M + H]⁺ No. Structure required found 8

411 412 9

397 398 10

431 432 11

376 377 12

368 369 13

390 391 14

376 377 15

387 388 16

367 368 17

387 388 18

424 425 19

422 423 20

401 402 21

354 355 22

354 355 23

336 337 24

342 343 25

387 388 26

411 412 27

404 405 28

458 459 29

356 357 30

431 432 31

367 368 32

324 325 33

353 354 34

392 393 35

368 369 36

385 386 37

376 377 38

384 385 39

336 337 40

340 341 41

398 399 42

412 413 43

412 413 44

390 391 45

390 391 46

386 387 47

422 423 48

429 430 49

449 450 50

429 430 51

405 406 52

382 383 53

382 383 54

415 416

1. A compound of the formula (I)

in which R¹ and R² are attached to adjacent phenyl ring atoms andtogether with the two ring carbon atoms form a 5- or 6-memberedsaturated or partially unsaturated ring which may contain one or twooxygen atoms and which may be mono- or disubstituted, independently ofone another, by (C₁–C₄)-alkyl which may be substituted by hydroxyl,(C₁–C₄)-alkoxy or phenyl; cyano; halogen; or oxo; R³ represents(C₁–C₈)-alkyl which may be substituted up to three times, independentlyof one another, by hydroxyl, (C₁–C₄)-alkoxy, (C₃–C₇)-cycloalkyl,(C₂–C₄)-alkenyl, (C₂–C₄)-alkynyl, halogen or (C₆–C₁₀)-aryloxy;(C₆–C₁₀)-aryl which may be substituted up to three times, independentlyof one another, by halogen, nitro, (C₁–C₄)-alkoxy, carboxyl,(C₁–C₄-alkoxycarbonyl or mono- or di-(C₁–C₄)-alkylamino; (C₁–C₈)-alkoxywhich may be substituted by hydroxyl, (C₁–C₄)-alkoxy,(C₃–C₆)-cycloalkyl, (C₂–C₄)-alkenyl, (C₆–C₁₀)-aryl, 5- to 10-memberedheteroaryl having up to three heteroatoms from the group consisting ofN, O and/or S, (C₆–C₁₀)-aryloxy, halogen, cyano, (C₁–C₄)-alkoxycarbonyl,amino or mono- or di-(C₁–C₄)-alkylamino; hydrogen; hydroxyl; halogen;nitro; cyano; or —NH—C(O)—R⁵;  in which R⁵ represents (C₁–C₈)-alkyl,which may be substituted by hydroxyl or (C₁–C₄)-alkoxy; or(C₃–C₇)-cycloalkyl or (C₆–C₁₀)-aryl, which may be substituted up tothree times, independently of one another, by halogen, nitro,(C₁–C₄)-alkoxy, carboxyl, (C₁–C₄)-alkoxycarbonyl or mono- ordi-(C₁–C₄)-alkylamino, and R⁴ represents (C₂–C₄)-alkenyl,(C₃–C₇)-cycloalkyl or (C₁–C₈)-alkyl, where alkyl may be substituted upto three times, independently of one another, by halogen,trifluoromethyl, trifluoromethylthio, (C₃–C₇)-cycloalkyl, hydroxyl,—CO—NH—R⁶, (C₁–C₄)-alkoxy, (C₁–C₄-alkoxycarbonyl, (C₂–C₄)-alkenyl,(C₆–C₁₀))-aryl or 5- to 10-membered heteroaryl having up to threeheteroatoms and/or hetero chain members selected from the groupconsisting of N, NO(N oxide), O and S,  where aryl and heteroaryl may besubstituted up to three times, independently of one another, by halogen;trifluoromethyl; (C₁–C₄)-alkyl which may be substituted by carboxyl or(C₁–C₄)-alkoxycarbonyl; (C₁–C₄)-alkoxy; carboxyl;(C₁–C₄)-alkoxycarbonyl; amino; mono- or di-(C₁–C₄)-alkylamino; nitro;cyano; or hydroxyl; and R⁶ represents hydrogen; (C₁–C₈)-alkyl which maybe substituted by hydroxyl or (C₁–C₄)-alkoxy; or (C₃–C₇)-cycloalkyl or(C₆–C₁₀)-aryl which may be substituted up to three times, independentlyof one another, by halogen, nitro, (C₁–C₄)-alkoxy, carboxyl,(C₁–C₄)-alkoxycarbonyl or mono- or di-(C₁–C₄)-alkylamino; or a salt, ahydrate, a hydrate of a salt or a solvate thereof.
 2. The compound asclaimed in claim 1, in which R¹ and R² are attached to adjacent phenylring atoms and together with the two ring carbon atoms form a 5- or6-membered saturated ring which may contain one or two oxygen atoms andwhich may be mono- or disubstituted, independently of one another, bymethyl which may be substituted by hydroxyl, (C₁–C₄)-alkoxy or phenyl;fluorine; or chlorine; R³ represents hydrogen or chlorine and R⁴represents (C₂–C₄)-alkenyl or (C₁–C₄)-alkyl, where alkyl may besubstituted up to two times, independently of one another, by halogen,trifluoromethyl, trifluoromethylthio, (C₃–C₇)-cycloalkyl, hydroxyl,—CO—NH—R⁶, (C₁–C₄)-alkoxy, (C₁–C₄)-alkoxycarbonyl, (C₂–C₄)-alkenyl,(C₆–C₁₀)-aryl or 5- or 6-membered heteroaryl having up to threeheteroatoms selected from the group consisting of N, O and S,  wherearyl and heteroaryl may be substituted up to three times, independentlyof one another, by halogen; trifluoromethyl; (C₁–C₄)-alkyl which may besubstituted by carboxyl or (C₁–C₄)-alkoxycarbonyl; (C₁–C₄)-alkoxy;carboxyl; (C₁–C₄)-alkoxycarbonyl; nitro; cyano; or hydroxyl; and R⁶represents hydrogen (C₁–C₄)-alkyl, or a salt, a hydrate, a hydrate of asalt or a solvate thereof.
 3. The compound as claimed in claim 1, inwhich R¹ and R² are attached to adjacent phenyl ring atoms and representa group

R³ represents hydrogen and R⁴ represents propenyl; methyl; ethyl; orn-propyl; where the alkyl radicals may be substituted up to two times,independently of one another, by hydroxyl, methoxy, trifluoromethyl,trifluoromethylthio, fluorine, imidazolyl, pyridyl, or phenyl which forits part may be substituted by fluorine, cyano, nitro, methoxy,methoxycarbonyl (—C(O)—O—CH₃) or methoxycarbonylmethyl (—CH₂—C(O)—CH₃);methoxycarbonyl (—C(O)—O—CH₃); amido (—C(O)—NH₂); or N-merhylamido(—C(O)—NH—CH₃); or a salt, a hydrate, a hydrate of a salt or a solvatethereof.
 4. The compound as claimed in claim 1 in which R¹ and R² areattached to adjacent phenyl ring atoms and represent a group

R³ represents hydrogen and R⁴ represents propenyl; methyl; ethyl; orn-propyl; where the alkyl radicals may be substituted up to two times,independently of one another, by hydroxyl, methoxy, trifluoromethyl,trifluoromethylthio, fluorine, imidazolyl, optionally methyl-substitutedthiazolyl, pyridyl, or phenyl which for its part may be substituted byfluorine, cyano, nitro, methoxy, methoxycarbonyl (—C(O)—O—CH₃) ormethoxycarbonylmethyl (—CH₂—C(O)—O—CH₃); methoxycarbonyl (—C(O)—O—CH₃);amido (—C(O)—NH₂); or N-methylamido (—C(O)—NH—CH₃); or a salt, ahydrate, a hydrate of a salt or a solvate thereof.
 5. The compound asclaimed in claim 1 in which R¹ and R² are attached to adjacent phenylring atoms and represent a group

R³ represents hydrogen and represents methyl; ethyl; or n-propyl; wherethe alkyl radicals may be substituted up to two times, independently ofone another, by hydroxyl, trifluoromethyl, trifluoromethylthio,fluorine, imidazolyl, optionally methyl-substituted thiazolyl, phenylwhich is substituted by cyano, nitro, methoxycarbonyl (—C(O)—O—CH₃) ormethoxycarbonylmethyl (—CH₂—C(O)—O—CH₃); or amido (—C(O)—NH₂); or asalt, a hydrate, a hydrate of a salt or a solvate thereof.
 6. A processfor preparing compounds of the formula (I) as defined in claim 1,characterized in that a compound of the formula (II)

 in which the radicals R¹, R² and R³ are as defined in claim 1, isreacted with a compound of the formula (III)R⁴—X  (III)  in which R⁴ is as defined in claim 1 and X represents aleaving group.
 7. A pharmaceutical composition comprising at least onecompound of the formula (I) as defined in claim 1 and at least onefurther auxiliary.
 8. A method for the treatment of disorders of thecardiovascular system (cardiovascular disorders) comprisingadministering an effective amount of a compound of the formula (I) asdefined in claim 1 wherein the cardiovascular disorders consists ofstable and unstable angina pectoris and atrial fibrillation.